The signaling pathway induced by fibroblast growth factors (FGFs) and their receptors, fibroblast growth factor receptors (FGFRs), is one of signaling pathways having the most important functions in the course of development from early embryogenesis to the formation of various organs. There are 18 genes of FGF ligands and four FGFR genes (FGFR1 to FGFR4), which are expressed in various cells and involved in cell growth, differentiation, and survival. In recent years, the importance of FGF signaling in the pathogenesis of diverse tumor types has been reported, and clinical reagents that specifically target the FGFs or FGF receptors are being developed (Nature Reviews Cancer 2010; 10, 116-129, J. Med. Chem. 2011; 54, 7066-7083, AACR 2011, No. 1643 AstraZeneca).
As for FGFR1, it is reported that FGFR1 gene is amplified in lung cancer (in particular, squamous cell cancer) and hormone therapy-resistant breast cancer, and it is also reported that these cell lines exhibit FGFR1-dependent cell growth (Sci. Transl. Med. 2010; 2(62): 62ra93, Breast Cancer Res. 2007; 9(2): R23, Cancer Res. 2010, 70 (5), 2085-2094).
As for FGFR2, the gene amplification in stomach cancer and triple negative breast cancer and the activating mutation in endometrial cancer are reported (Laboratory Investigation 1998, 78(9); 1143-1153, Virchows Arch. 1997, 431; 383-389, J. Cancer Res. Clin. Oncol., 1993, 119, 265-272, AACR 2011, No. 1643 AstraZeneca, Oncogene 2010; 29, 2013-2023). These cancer cells have been also confirmed to exhibit FGFR2-dependent growth.
Further, FGFR3 exhibits activating gene mutation in about 50% of cases of bladder cancer. Bladder cancer is largely divided into three types: non-invasive, invasive, and metastatic types. There have been issues on them that although non-invasive bladder cancer has a high 5-year survival rate of 70% or above, it frequently recurs or partly progresses to invasive cancer, and that invasive or metastatic bladder cancer has a low 5-year survival rate of 50% or below. Current therapies for non-invasive bladder cancer with FGFR3 mutation are transurethral resection of bladder tumor (TUR-BT) and postoperative BCG therapy or intravesical instillation of chemotherapeutic agents. However, their recurrence-preventing effect remains unsatisfactory, and their adverse effects such as hematuria and irritable bladder have been at issue. Meanwhile, total cystectomy and the systemic administration of chemotherapeutic agents have been used for the treatment of invasive or metastatic bladder cancer. However, there are issues on their effectiveness, and adverse effects. Bladder cancer is known to be characterized in that part of the cancer cells sloughs off from bladder tissues into urine, and, based on this characteristic, urine cytology is used for the diagnostic of bladder cancer. It was recently reported that FGFR3 mutation can be detected using the sediments in urine (Biochem. Biophys. Res. Commun. Nov. 3, 2007; 362(4): 865-71). Based on the presence or absence of this FGFR3 mutation, patients with FGFR3 mutation-positive bladder cancer can be selected, and the creation of an FGFR3 selective inhibitor has been demanded.
It is also reported that fusion genes combining FGFR genes and TACC (Transforming Acidic Coiled-coil) genes (FGFR3-TACC3 and FGFR1-TACC1) are expressed in the tumor of some glioblastoma patients (Science, Sep. 7, 2012; 337(6099): 1231-5). According to this report, the forced expression of FGFR3-TACC3 and FGFR1-TACC1 in astrocytes led to transformation and this result showed the oncogenicity of these fusion genes. It was also shown that FGFR3-TACC3 is localized in mitotic spindle poles and induces kinase activity-dependent chromosomal aneuploidy. Further, treatment of FGFR3-TACC3-expressing cells with an FGFR inhibitor suppressed chromosomal aneuploidy, thereby suppressing the growth of the cells. Thus, it is suggested that FGFR inhibitors might be effective for the treatment of glioblastoma patients with FGFR-TACC fusion genes.
It is also reported that human bladder cancer cell lines RT112, RT4, and LUCC2 express FGFR3-TACC3 fusion gene and that human bladder cancer cell line SW780 also expresses FGFR3-BAIAP2L1 fusion gene (Hum Mol Genet., 2013 Feb. 15, 22(4), 795-803). According to this report, the anchorage-independent growth of these fusion genes has been confirmed as a result of their introduction into NIH3T3 cells. Given that the growth of the foregoing bladder cancer cell lines expressing these FGFR3 fusion genes is inhibited by FGFR inhibitors, the detection of the presence of the fusion genes can be useful to select patients who can be treated effectively with FGFR inhibitors.
It is reported that the compounds of formula (A) shown below exhibit inhibition of various kinases and are useful as therapeutic agents for cancer and vascular disorders including myocardial infarction (Patent Document 1). Table 2 of the document discloses the test results of inhibition of kinases Yes, VEGFR, EphB4, PDGFRβ, and FGFR1 by some of the compounds, which discloses that IC50 values for the FGFR1 inhibitory activity were higher than 1000 nM, showing that the activity was also lower than in the case of inhibition of the activity of the other kinases. Further, in the document, there is no specific disclosure about the compounds of formula (I) of the present invention described below.
(In this formula, each of A is CH, N, or the like; each of B is CH or the like; A1 is O, CR2, or the like; R0 is H or the like; A2 is NR, O, or the like; L1 is a bond, O, or the like; L2 is a bond, C1-C6 alkyl, or the like; R1 is a 3- to 6-membered heterocyclic ring or the like; and each of Re and Rf is H, C1-C6 alkyl, hydroxyalkyl, or the like. For the other symbols, refer to the publication.)
It is reported that the compounds of formula (B) shown below exhibit Abl inhibitory action and are useful against various cancers (Patent Document 2). However, in the document, there is no specific description about FGFR inhibitory action. Further, the compounds of formula (I) of the present invention described below have group (R1)p which differentiate the compounds in structure from the compounds of formula (B).
(In this formula, G is CH or the like; A is 3-hydroxyphenyl or the like; and Y is vinyl or ethylene. For the other symbols, refer to the publication.)
It is reported that the compounds of formula (C) shown below have inhibitory action on various kinases including Src, VEGFR2, Yes, Fyn, Lck, Abl, PDGFR, EGFR, and RET and are usable for the treatment of cancer, vascular disorders, and the like (Patent Document 3). However, there is no disclosure about FGFR inhibitory action in the document. In the document, there is also no specific disclosure about the compounds of formula (I) of the present invention described below.
(In this formula, G1 is aryl optionally having a substituent, heteroaryl optionally having a substituent, or the like; L1 is O, SO, SO2, optionally substituted alkyl, or the like; L2 is optionally substituted alkyl, heterocyclic ring, or the like; A1 is a bond, O, C(Ra)2, or the like; and A2 is NRa, O, or the like. For the other symbols, refer to the publication.)
It is reported that the compounds of formula (D) shown below have TIE-2 and/or VEGFR-2 kinase inhibitory action and are useful in treatment of angiogenesis-related diseases including cancer (Patent Document 4). However, there is no specific description about FGFR inhibition in the document. Further, the compounds of formula (I) of the present invention described below differ in structure from the compounds of formula (D) in that the compounds of formula (I) have a group L1 having no amino group and that the compounds also have two bonds positioned para to each other on a ring comprising X and Y.
(In this formula, W is N or CR; R is H or the like. For the other symbols, refer to the publication.)
It is reported that the compounds of formula (E) shown below exhibit inhibitory action on the activity of many receptor protein tyrosine kinases, particularly, FGFRs, and can be used for the treatment of various diseases related to aberrant or excessive activity of these enzymes (Patent Document 5). However, the compounds of formula (I) of the present invention described below differ in structure from the compounds of formula (E) in that the compounds of formula (I) have a group L1 which does not represent a N atom and that the compounds also have two bonds positioned para to each other on a ring comprising X and Y.
(In this formula, two of X, Y, and Z are N and the third is CH or N. For the other symbols, refer to the publication.)
It is reported that the compounds of formula (F) shown below exhibit inhibitory action on various kinases and are useful against inflammation and autoimmune diseases (Patent Document 6). On the other hand, the compounds of formula (I) of the present invention described below differ in structure from the compounds of formula (F) in that the compounds of formula (I) have a group L1 which is not amide and that the compounds also have two bonds positioned para to each other on a ring comprising X and Y.
(In this formula, A1, A2, A3, and A4 are CR4, CR5, CR6, and CR7, respectively, or are N; L is —C(O)NR7—, —NR7C(O)—, or the like. For the other symbols, refer to the publication.)
It is reported that the compounds of formula (G) and those of formula (H) shown below exhibit FGFR inhibitory action and can be used for the treatment of various cancers (Patent Documents 7 and 8).
(In formula (G), ring B represents a 5- or 6-membered aromatic group that may comprise at least one heteroatom selected from O, S, and N. For the other symbols, refer to the publication.)
It is reported that the compounds of formula (J) shown below exhibit glucokinase activating effects and can be used for the treatment of diseases related to diabetes mellitus (Patent Document 9), and the structural feature is substitution with amino at the 2 position of the pyridine.
(For the symbols in this formula, refer to the publication.)
Also, the known compounds having the structures shown below are registered on the database as 1371065-79-0 and 1317903-92-6 in CAS registry number, respectively.
